There is a growing body of data linking excessive iron stores with a number of chronic conditions that are common to the elderly population, e.g., ischemic heart disease, cancer, and rheumatic disease. Whether routine blood donations to lower iron stores of elderly individuals reduces the risk for developing chronic conditions remains to be tested. We have conducted studies to determine whether elderly individuals can become regular blood donors without ill effects. Our results have been published in a series of articles and summarized as follows: 1. Iron stores in elderly individuals exceed that found in younger adults. 2. Elderly individuals tolerate blood donations well. 3. There is a large- between subject variation in iron stores that cannot be attributed to differences in diet or disease conditions. 4. In blood donors, there is a significant linear relationship between increases in iron absorption and decreases in iron stores from predonation levels, regardless of whether they started with low or high iron stores. These results indicate that iron absorption is regulated by the depletion of iron stores from genetically determined steady-state levels. The underlying hypothesis for the experiments outlined in this proposal is that the proteins responsible for cellular iron uptake and storage are genetically controlled and explain the wide variations in iron stores noted in elderly individuals. The specific aims of this proposal is to determine whether the current elderly population with high, medium, and low steady-state stores segregate with respect to genes that control iron uptake and storage, e.g. transferrin receptor, ferritin, and iron responsive element binding protein (IRE-BP). In addition, it will be determined if high and/or low iron stores are genetically transmitted in families of these elderly subjects. If linkage of iron stores is found to a cloned iron metabolism gene, SSCP screening assays will be used to detect sequence alterations in the gene(s) of interest, focussing initially on likely regions such as iron response elements. Correlation of iron store levels with mRNA and protein levels for iron metabolism genes will also be assessed.